Guest editorial: special issue on bone tissue engineering

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Bioactive composites for bone tissue engineering

One of the major challenges of bone tissue engineering is the production of a suitable scaffold material. In this review the current composite materials options available are considered covering both the methods of both production and assessing the scaffolds. A range of production routes have been investigated ranging from the use of porogens to produce the porosity through to controlled deposition methods. The testing regimes have included mechanical testing of the materials produced through to in vivo testing of the scaffolds. While the ideal scaffold material has not yet been produced, progress is being made

Dissolution and Mechanical properties of Bioresorbable Glass Fibres for use in Paediatric tracheal stents

Stents provide biological support in body conduits and are useful for counteracting stenosis (constriction) in cardiovascular, gastrointestinal, uretheral and airway passages1. However, the current widespread use of permanent metal stents that remain throughout the lifespan of a patient, threaten restenosis, thrombosis, or physical irritation if not surgically removed. In infants the clinical requirement is for a stent that retains structural integrity for periods of several weeks up to many months in vivo during host tissue restoration2 and from a materials perspective this requires an implant with appropriate mechanical and degradation characteristics. Bioresorbable phosphate glass fibres have shown enormous potential for temporary implants and tissue repair, owing to their mechanical properties and solubility in aqueous media which can be modified by addition of various oxide compounds3,4. Further, when combined with degradable polymers the resulting glass fibre polymer composites (GFRP) become ductile allowing them to be forged into supporting scaffolds with suitable mechanical and dissolution properties. To date however, their use for stenting applications has not been investigated possibly due to major difficulties of processing these compositions into fibre form. In this study, two phosphate glass fibre compositions containing SiO2 (silica) and B2O3 (Boron) were fabricated to test the hypothesis that B2O3 containing phosphate glass fibres present enhanced mechanical and dissolution behaviour for use as a degradable stent

Prediction of risk of fracture in the tibia due to altered bone mineral density distribution resulting from disuse : a finite element study

The disuse-related bone loss that results from immobilisation following injury shares characteristics with osteoporosis in postmenopausal women and the aged, with decreases in bone mineral density (BMD) leading to weakening of the bone and increased risk of fracture. The aim of the study was to use the finite element method to: (i) calculate the mechanical response of the tibia under mechanical load and (ii) estimate the risk of fracture; comparing between two groups, an able bodied (AB) group and spinal cord injury (SCI) patients group suffering from varying degree of bone loss. The tibiae of eight male subjects with chronic SCI and those of four able-bodied (AB) age-matched controls were scanned using multi-slice peripheral Quantitative Computed Tomography. Images were used to develop full three-dimensional models of the tibiae in Mimics (Materialise) and exported into Abaqus (Simulia) for calculation of stress distribution and fracture risk in response to specified loading conditions – compression, bending and torsion. The percentage of elements that exceeded a calculated value of the ultimate stress provided an estimate of the risk of fracture for each subject, which differed between SCI subjects and their controls. The differences in BMD distribution along the tibia in different subjects resulted in different regions of the bone being at high risk of fracture under set loading conditions, illustrating the benefit of creating individual material distribution models. A predictive tool can be developed based on these models, to enable clinicians to estimate the amount of loading that can be safely allowed onto the skeletal frame of individual patients who suffer from extensive musculoskeletal degeneration (including SCI, multiple sclerosis and the ageing population). The ultimate aim would be to reduce fracture occurrence in these vulnerable groups

Biomechanical properties of bone in a mouse model of Rett syndrome

Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (<i>MECP2</i>) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, <i>MECP2</i> is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional knockout mouse model of RTT. Both hemizygous <i>Mecp2</i><sup>stop/y</sup> male mice in which <i>Mecp2</i> is silenced in all cells and female <i>Mecp2</i><sup>stop/+</sup> mice in which <i>Mecp2</i> is silenced in ~ 50% of cells as a consequence of random X-chromosome inactivation, revealed significant reductions in cortical bone stiffness, microhardness and tensile modulus. Microstructural analysis also revealed alterations in both cortical and cancellous femoral bone between wild-type and MeCP2-deficient mice. Furthermore, unsilencing of <i>Mecp2</i> in adult mice cre-mediated stop cassette deletion resulted in a restoration of biomechanical properties (stiffness, microhardness) towards wild-type levels. These results show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies

Hybrid Core-Shell Scaffolds for Bone Tissue Engineering

The tissue engineering applications of coaxial electrospinning are growing due to the potential increased functionality of the fibres compared to basic electrospinning. Previous studies of core and shell scaffolds have placed the active elements in the core, however, the surface response to a biomaterial affects the subsequent behaviour, thus here hydroxyapatite (HA) was added to the shell. Coaxial electrospun polycaprolactone (PCL)-polylactic acid (PLA)/HA (core-shell) scaffolds were produced in 2D sheets using a plate collector, or 3D tubes for bone tissue engineering using a rotating needle collector. The scaffolds include high hydroxyapatite content while retaining their structural and mechanical integrity. The effect of the collector type on fibre diameter, fibre alignment and mechanical properties have been evaluated, and the impact of HA incorporation on bioactivity, BMP-2 release, cell behaviour and mechanical properties for up to 12 weeks degradation were assessed. Fibre uniformity in coaxial electrospinning depends on the relative flow rate of the core and shell solutions. Using a rotating needle collector increased fibre alignment compared to a stationary collector, without affecting fibre diameter significantly, while HA content increased fibre non-uniformity. Coaxial PCL-PLA/HA fibres exhibited significantly higher bioactivity compared to PCL-PLA scaffolds due to the surface exposure of the HA particles. Apatite formation increased with increasing SBF immersion time. Coaxial tubular scaffolds with and without HA incorporation showed gradual reductions in their mechanical properties over 12 weeks in PBS or SBF but still retained their structural integrity. Coaxial scaffolds with and without HA exhibited gradual and sustained BMP-2 release and supported MSCs proliferation and differentiation with no significant difference between the two scaffolds types. These materials therefore show potential applications as bone tissue engineering scaffolds

Self-folding nano- and micropatterned hydrogel tissue engineering scaffolds by single step photolithographic process

Current progress in tissue engineering is focused on the creation of environments in which cultures of relevant cells can adhere, grow and form functional tissue. We propose a method for controlled chemical and topographical cues through surface patterning of self-folding hydrogel films. This provides a conversion of 2D patterning techniques into a viable method of manufacturing a 3D scaffold. While similar bilayers have previously been demonstrated, here we present a faster and high throughput process for fabricating self-folding hydrogel devices incorporating controllable surface nanotopographies by serial hot embossing of sacrificial layers and photolithography

Pharmacists Are Not Mid-Level Providers

Pharmacists should not be classified as “mid-level” providers. This classification implies that there are different levels or a hierarchy of providers when in fact each health care provider brings unique and essential knowledge and contributions to the health care team and to the care of patients. Pharmacists are no exception. Timely issues germane to pharmacists, including dependent and independent practice, provider status, and professional identity, contribute to the rationale that pharmacists, just like all other health care providers, should be classified by their professional identity. While use of the term mid-level provider to identify various practitioners may not seem consequential, in today’s health care environment, words do matter when it comes to attributing value, and the contributions of all health care providers should be recognized as equally important to the patient care team

The skeletal phenotype of chondroadherin deficient mice

Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their a2b1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3–6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the a1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro-CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth

Web-Based Genome-Wide Association Study Identifies Two Novel Loci and a Substantial Genetic Component for Parkinson's Disease

Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD–rs6812193 near SCARB2 (, ) and rs11868035 near SREBF1/RAI1 (, )—both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%–7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered